Triterpenoids are biosynthesized in plants by the cyclization of squalene. Although being candidates for medicinal use, these naturally occurring molecules display relatively weak biological activity. Accordingly, chemists have sought to synthesize analogues of enhanced potency (Honda et al, 1997 & 1998).
Several synthetic analogs are reported to suppress the denovo formation of cytokine-inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in macrophages that have been stimulated by IFN-γ or LPS (Suh et al, 1998; Honda et al, 2002). Among them, 2-cyano-3,12-dioxoleana-1,9(11)-dien-28-oate (CDDO), exhibits anti-inflammatory and anti-proliferative activity (Honda et al, 1998 & 2000). As noted, the study of triterpenoids as suppressors of iNOS activity, and specifically in the inhibition of NO production, has demonstrated the high potency of CDDO and CDDO methyl ester (IC50<1 nM level). See Honda et al. (2000). However, their therapeutic potential is believed to be not yet fully utilized, even less so for CDDO ethyl ester.
To realize the therapeutic potential of CDDO ethyl ester, depicted in Formula I, the present inventors investigated polymorphic forms of the compound. Consequently, the inventors discovered three polymorphic forms of CDDO ethyl ester, that have such advantageous properties (e.g., better pharmacokinetic profiles and greater systemic exposure) that make them ideal candidates for drug development.